Several provocative leads point not only to the role of 5HT receptors in mediating the therapeutic actions of antidepressant drugs, but also to being the possible site of a biochemical lesion in untreated patients with major depressive disorder. The general goal of this application is to apply platelet and neuroendocrine methods to measure adaptive responses to specific human 5HT receptor subtypes to chronic tricyclic antidepressant treatment. The specific aims are (1) to develop more selective methods for studying specific 5HT receptor subtypes in man; (2) to clarify the 5HT receptor subtype selectively (if any) of neuroendocrine probes widely used in the literature; and (3) to determine if chronic antidepressant drug treatment causes adaptive responses in selective markers of 5HT1A and 5HT2 receptor subtypes in normal control subjects. Firstly, these studies will evaluate the role of 5HT1 receptors in the actions of the nonselective 5HT indirect agonist fenfluramine by determining if the 5HT1 (and beta adrenergic) antagonist pindolol blocks any of four measures induced by fenfluramine which could be mediated in part or in full by 5HT1 receptors: hypothermic response and rises in ACTH, cortisol and prolactin. Secondly, these studies will evaluate possible specific adaptive responses of 5HT1A and 5HT2 receptor subtypes to chronic tricyclic antidepressant drug treatment and withdrawal in normal control subjects. This will be done by determining whether 5HT1A pre-synaptic somatodendritic autoreceptors - as measured by hypothermia induced by the selective 5HT1A partial agonist ipsapirone - and/or post synaptic 5HT1A receptors - as measured by ipsapirone-induced rises in ACTH/cortisol - exhibit detectable adaptive responses to chronic nortriptyline treatment and withdrawal in normal volunteers. Thirdly, these studies will determine whether 5HT2 receptors - as measured by 125I-LSD binding and by the platelet shape change response to 5HT - exhibit detectable adaptive responses to chronic nortriptyline treatment and withdrawal in normal volunteers. These investigations should generate important pilot data to determine the feasibility and design to future studies to link adaptive responses of 5HT1A and 5HT2 receptors to therapeutic actions of antidepressant drug treatment of depressed patients.